7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

“…Several triazolo[1,5‐a]pyrimidines, 1,2,4‐triazolo[1,5‐a]pyrazines, pyrazolo[3,4‐ d ]pyrimidines, pyrazolo[4,3‐ d ]pyrimidines, and pyrrolo[2,3‐d]pyrimidines have been considered as possible bioisosters of the triazolotriazine template, but a general decrease in A 2A AR binding affinity and/or selectivity was found, with the exception of 64 developed by Schering‐Plough (Fig. ).…”

“…The second-generation lead gave evidence for a promising safety and pharmacokinetic profile in healthy volunteers during a Phase I trial (see Section 6). 101 Some C 2 -, N 7 -, and N 9 -trisubstituted-purin-8-ones (i.e., 54 K i hA 2A AR = 9 nM, K i hA 1 AR = 1967, IC 50 rA 2A AR = 18 nM), 175 2-alkynyl-N 9 -propargyl adenine derivatives (i.e., 55 K i hA 2A AR = 0.56 nM, K i hA 2B /K i hA 2A ARs = 1.300, K i hA 1 /K i hA 2A ARs = 10), 176,177 and 7-amino-2-arylpyrazolo[4,3-d]pyrimidine derivatives (i.e., 56, K i hA 2A AR = 55 nM, K i hA 1 AR = 5.3 nM) 178 have been reported as examples of purine-related A 2A antagonists or A 1 /A 2A dual antagonists.…”

The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles

“…The new 5-phenyl(alkyl)amino derivatives 1 , 5 and 6 were designed as analogs of our previously reported antagonists 5-phenyl(alkyl) derivatives A , B and C 24 whose methylene linker at the 5-position of the bicyclic core was replaced with an NH. This modification, suggested by the structure of potent A 2A antagonists bearing arylalkylamino moieties as key substituents 12 , was thought to change the flexibility of the 5-lateral chain and, hopefully, to increase the affinity for the targeted ARs.…”

“…In our laboratory, much research has been addressed to the study of AR antagonists belonging to different classes 15–26 , including the 2-arylpyrazolo[4,3- d ]pyrimidine derivatives 20 , 22 , 24 , 26 which display a broad range of affinity for the various AR subtypes, depending on the nature of the substituents at the 5- and 7-positions of the bicyclic scaffold. One recent study aimed at targeting the A 1 and A 2A ARs highlighted that the presence of a free 7-amino group, combined with a benzyl or, even better, a 3-phenylpropyl chain at the 5-position ( Figure 1 , compounds A and C ) shifted affinity toward these two AR subtypes 24 .…”

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

“…12,[22][23][24][25] However, at present the antinociceptive activity of AR antagonists such as caffeine is in contrast with the more documented pain-protective action exerted by AR agonists, in particular compounds targeting the A 1 subtype. 10,11,15,16,18,19 In our laboratory, much research has been addressed to the study of AR ligands belonging to different chemical classes [26][27][28][29][30][31][32][33][34][35][36][37] including the recently reported amino-3,5-dicyanopyridine series. 37 These derivatives were designed as hA 2B AR agonists although special attention was devoted to deepening the structure-activity relationships (SARs) of this chemical class.…”